Lymphocyte homing from the circulation to the lymphoid tissues and migration to sites of inflammation is regulated by interaction with receptors expressed in postcapillary venules, including high endothelial venules (HEV) found in secondary lymphoid tissues (e.g., mesenteric lymph nodes, Peyer's Patches (PP)) (Bevilacqua, M. P., Annu. Rev. Immunol., 11:767-804 (1993); Butcher, E. C., Cell, 67: 1033-1036 (1991); Picker, L. J., et al., Annu. Rev. Immunol., 10:561-591 (1992); and Springer, T. A., Cell, 76: 301-314 (1994)). These interactions are tissue specific in nature.
Inflammation (e.g., chronic inflammation) is characterized by infiltration of the affected tissue by leukocytes, such as lymphocytes, lymphoblasts, and mononuclear phagocytes. The remarkable selectivity by which leukocytes preferentially migrate to various tissues during both normal circulation and inflammation results from a series of adhesive and activating events involving multiple receptor-ligand interactions as proposed by Butcher and others (Butcher, E. C., Cell, 67: 1033-1036 (1991); vonadrian, U. H., et al., Proc. Natl. Acad. Sci. USA, 88:7538 (1991); Mayadas, T. N., et al., Cell, 74:541 (1993); (Springer, T. A., Cell, 76:301 (1994)). As an initial step, there is a transient, rolling interaction between leukocytes and endothelium, which results from the interaction of selectins (and by .alpha.4 integrins in some instances) with their carbohydrate ligands. This interaction, which is characterized by rolling in the direction of flow, can be assessed by known methods (Lawrence, M. B. and T. A. Springer, Cell, 65:859 (1991); WO 92/21746, Springer et al., (Dec. 10, 1992)). This is followed by activation events mediated by chemoattractants such as chemokines and their receptors, which cause activation of integrin adhesiveness and influence the direction of migration of leukocytes through vascular walls. Such secondary signals in turn trigger the firm adhesion of leukocytes to endothelium via leukocyte integrins and their endothelial ligands (Ig-like receptors and the ECM), and subsequent transendothelial migration from the circulation across the vascular endothelium.
In secondary lymphoid tissues, such as Peyer's patches (PPs) and lymph nodes (e.g., peripheral lymph nodes (PLN)), leukocyte trafficking and homing is regulated by interactions of homing receptors on the surface of leukocytes with endothelial cells lining the post-capillary venules, notably high endothelial venules (HEV) (Gowans, J. L. and E. J. Knight, Proc. R. Soc. Lond., 159:257 (1964)). Receptors termed vascular addressing, which are present on the endothelial cell surface and regulate the migration and subsequent extravasation of lymphocyte subsets. The vascular addressins show restricted patterns of expression and this tissue specific expression makes an important contribution to the specificity of leukocyte trafficking (Picker, L. J. and E. C. Butcher, Annu. Rev. Immunol., 10:561-591 (1992); Berg, E. L., et al., Cellular and molecular mechanisms of inflammation, 2:111 (1991); Butcher, E. C., Cell, 67:1033-1036 (1991)).
Mucosal vascular addressin MAdCAM-1 (Mucosal Addressin Cell Adhesion Molecule-1) is an immunoglobulin superfamily adhesion receptor for lymphocytes, which is distinct from VCAM-1 and ICAM-1. MAdCAM-1 was identified in the mouse as a .sup..about. 60 kd glycoprotein which is selectively expressed at sites of lymphocyte extravasation. In particular, MAdCAM-1 expression was reported in vascular endothelial cells of mucosal tissues, including gut-associated tissues or lymph of the small and large intestine, and the lactating mammary gland, but not in peripheral lymph nodes. MAdCAM-1 is involved in lymphocyte binding to Peyer's Patches. (Streeter, P. R., et al., Nature, 331:41-46 (1988); Nakache, M., et al., Nature, 337: 179-181 (1989); Picker, L. J., et al., Annu. Rev. Immunol., 10:561-591 (1992); Briskin, M. J., et al., Nature, 363:461 (1993); Berg, E. L., et al., Nature, 366:695-698 (1993); Berlin, C., et al., Cell, 74:185-195 (1993)). MAdCAM-1 can be induced in vitro by proinflammatory stimuli (Sikorski, E. E., et al., J. Immunol., 151:5239-5250 (1993)). cDNA clones encoding murine and primate (e.g., human) MAdCAM-1 have been isolated and sequenced (Briskin, M. J. et al., Nature, 363: 461-464 (1993); Briskin et al., WO 96/24673, published Aug. 15, 1996; and Briskin, M. J. et al., U.S. Ser. No. 08/523,004, filed Sep. 1, 1995, the teachings of each of which is incorporated herein by reference in its entirety).
MAdCAM-1 specifically binds the lymphocyte integrin .alpha.4.beta.7 (also referred to as LPAM-1 (mouse), .alpha.4.beta.p (mouse)), which is a lymphocyte homing receptor involved in homing to Peyer's patches (Berlin, C., et al., Cell, 80:413-422 (1994); Berlin, C., et al., Cell, 74:185-195 (1993); and Erle, D. J., et al., J. Immunol., 153: 517-528 (1994)). In contrast to VCAM-1 and fibronectin, which interact with both .alpha.4.beta.1 and .alpha.4.beta.7 (Berlin, C., et al., Cell, 74: 185-195 (1993); Strauch, U.S., et al., Int. Immunol., 6:263 (1994)), MAdCAM-1 is a selective ligand for .alpha.4.beta.7 receptor.
Inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, for example, can be a debilitating and progressive disease involving inflammation of the gastrointestinal tract. Affecting an estimated two million people in the United States alone, symptoms include abdominal pain, cramping, diarrhea and rectal bleeding. IBD treatments have included anti-inflammatory drugs (such as corticosteroids and sulfasalazine), immunosuppressive drugs (such as 6-mercaptopurine, cyclosporine and azathioprine) and surgery (such as, colectomy). Podolsky, New Engl. J. Med., 325:928-937 (1991) and Podolsky, New Engl. J. Med., 325:1008-1016 (1991). There is a need for inhibitors of MAdCAM-1 function to provide new therapies useful in the treatment of IBD and other diseases involving leukocyte infiltration of the gastrointestinal tract or other mucosal tissues.